1. Description of the Related Art
.alpha.-Aminophosphonic acids and their derivatives are gaining greater and greater importance, e.g. as enzyme inhibitors, in biochemistry, pharmaceutical chemistry and in the field of plant protection [P. Kafarski, B. Lejczak, Phosph., Sulfur, and Silicon, 63 (1991)193]. There is a whole range of processes for the synthesis of this class of compound, which have been summarized in various reports [Kukhar and Solodenko, Russ. Chem. Rev. 56 (1987) 859, Redmoore, Topics in Phosphorus Chemistry, Vol. 11, Grayson and Griffith, Ed., Wiley 1976, 515].
The preparation of another class of compound, bis(aminomethyl)phosphinic acid and its derivatives, which are likewise of increasing importance in pharmaceutical chemistry (EP 0435059 A1), is far more complicated and only documented to a small extent. The synthesis of the parent compound was described for the first time by Meier [L. Meier, J. Organomet. Chem. 178 (1979) 157, DE 2805074A1, see also Kober et al., DE 3824961A1]. One possibility for the preparation of .alpha.- or .alpha.,.alpha.'-substituted derivatives of bis(aminomethyl)phosphinic acid is described by Tyka et al. [Phosphorus, Sulfur, and Silicon 62 (1991) 75]. The method is based on the addition of hypophosphorous acid to Schiff bases with formation of aminoalkylphosphonous acids in the first step, which are then reacted in the following step with arylidene bisamides to give .alpha.,.alpha.-bis(aminoalkyl)phosphinic acids. This process, however, is limited to the reaction with arylidene bisamides and is furthermore characterized by moderate yields. Only moderate yields were also observed for the double addition of hypophosphorous acid to Schiff bases with the formation of .alpha.,.alpha.'-bis(aminoalkyl)phosphinic acids. A further process [A. Peyman et al., Tetrahedron Lett. 33 (1992) 4549] is based on the alkylation of bis(aminomethyl)phosphinic acid, but in this way only radicals can be introduced which are accessible to nucleophilic substitution. Surprisingly, it has been found that many compounds can be prepared advantageously by alkylations of reverse polarity.
2. Summary of the Invention
The invention accordingly relates to a process for the preparation of compounds of the formula VI ##STR4## in which R.sup.2 and R.sup.3, independently of one another, are hydrogen, (C.sub.1 -C.sub.18)-alkyl, (C.sub.2 -C.sub.18)-alkenyl, (C.sub.2 -C.sub.18)-alkynyl, where alkyl, alkenyl and alkynyl can in each case be substituted one or more times by fluorine, chlorine, bromine, COOH, oxo, NO.sub.2, NH.sub.2, NHC(O)--(C.sub.1 -C.sub.6)-alkyl, NHC(O)--(C.sub.6 -C.sub.12)-aryl, CN, OH, CHO, CH--[(C.sub.1 -C.sub.6)-alkoxy].sub.2, COOH, SO.sub.3 H, C(O)--O--(C.sub.1 -C.sub.6)-alkyl, C(O)--O--(C.sub.6 -C.sub.12)-aryl, C(O)--(C.sub.1 -C.sub.6)-alkyl, C(O)--(C.sub.6 -C.sub.12)-aryl, O--C(O)--(C.sub.1 -C.sub.6)-alkyl, O--C(O)--(C.sub.6 -C.sub.12)-aryl, (C.sub.1 -C.sub.6)-alkoxy, are (C.sub.6 -C.sub.12)-aryl, (C.sub.7 -C.sub.22)-arylalkyl, where aryl can be substituted one or more times by fluorine, chlorine, bromine, NO.sub.2, NH.sub.2, NHC(O)--(C.sub.1 -C.sub.6)-alkyl, NHC(O)--(C.sub.6 -C.sub.12)-aryl, CN, OH, COOH, (C.sub.1 -C.sub.6)-alkyl, (C.sub.1 -C.sub.6)-alkoxy, C(O)--O--(C.sub.1 -C.sub.6)-alkyl, C(O)--O--(C.sub.6 -C.sub.12)-aryl, C(O)--(C.sub.1 -C.sub.6)-alkyl, C(O)--(C.sub.6 -C.sub.12)-aryl, O--C--(O)--(C.sub.1 -C.sub.6)-alkyl, O--C(O)--(C.sub.6 -C.sub.12)-aryl, or are P(O)[OH].sub.2, P(O)(OR.sup.23).sub.2, where R.sup.23 independently of one another is (C.sub.1 -C.sub.6)-alkyl, (C.sub.6 -C.sub.12)-aryl or (C.sub.7 -C.sub.13)-arylalkyl and where aryl can be substituted one or more times by fluorine, chlorine, bromine, NO.sub.2, CN, OH, COOH, (C.sub.1 -C.sub.6)-alkyl, (C.sub.1 -C.sub.6)-alkoxy, C(O)--O--(C.sub.1 -C.sub.6)-alkyl, C(O)--O--(C.sub.6 -C.sub.12)-aryl, C(O)--(C.sub.1 -C.sub.6)-alkyl, C(O)--(C.sub.6 -C.sub.12)-aryl, O--C(O)--(C.sub.1 -C.sub.6)-alkyl or O--C(O)--(C.sub.6 -C.sub.12)-aryl, where R.sup.2 and R.sup.3 are not simultaneously hydrogen,
R.sup.4 is a protective group for the amino function and R.sup.5 is (C.sub.1 -C.sub.18)-alkyl, (C.sub.2 -C.sub.18)-alkenyl, (C.sub.2 -C.sub.18)-alkynyl, (C.sub.6 -C.sub.12)-aryl, (C.sub.7 -C.sub.20)-arylalkyl, where alkyl, alkenyl, alkynyl and aryl can be substituted one or more times by fluorine, chlorine, bromine, oxo, NO.sub.2, NH.sub.2 or protected form, CN, OH, COOH, (C.sub.1 -C.sub.6)-alkyl, (C.sub.1 -C.sub.6)-alkoxy, C(O)--O--(C.sub.1 -C.sub.6)-alkyl, C(O)--O--(C.sub.6 -C.sub.12)-aryl, C(O)--(C.sub.1 -C.sub.6)-alkyl, C(O)--(C.sub.6 -C.sub.12)-aryl, O--C(O)--(C.sub.1 -C.sub.6)-alkyl, O--C(O)--(C.sub.6 -C.sub.12)-aryl,
which comprises converting a compound of the formula IV ##STR5## in which R.sup.4 and R.sup.5 have the abovementioned meaning and R.sup.6 and R.sup.7 independently of one another are H, Cl or Br, where not both radicals are simultaneously hydrogen
a) by reaction with a base to a compound of the formula Va or Vb ##STR6## where R.sup.4 and R.sup.5 have the abovementioned meanings and for the preparation of the compound VI a compound of the formula Va or Vb is reacted with carbon nucleophiles, or
b) the compound of the formula VI is prepared by direct reaction of a compound of the formula IV with R.sup.2.sub.2 Cu(CN)Li.sub.2, R.sup.2 Li, R.sup.2 MgX, R.sup.2 ZnX, R.sup.2.sub.2 Zn, R.sup.2.sub.4-n TiR.sup.22.sub.n (n&lt;4) P[O--R.sup.23 ].sub.3, where R.sup.2 has the abovementioned meaning, R.sup.22 is N--[(C.sub.1 -C.sub.6)-alkyl].sub.2, O--(C.sub.1 -C.sub.6)-alkyl, O--(C.sub.6 -C.sub.12)-aryl, where aryl can be substituted by fluorine, chlorine, bromine, NO.sub.2 NH.sub.2 or protected form, CN, OH, COOH, C(O)--O--(C.sub.1 -C.sub.6)-alkyl, (C.sub.1 -C.sub.6)-alkyl, (C.sub.1 -C.sub.6)-alkoxy, or is a tartaric acid derivative and R.sup.23 is (C.sub.1 -C.sub.6)-alkyl, (C.sub.6 -C.sub.12)-aryl, (C.sub.7 -C.sub.13)-arylalkyl, where aryl can be substituted one or more times by fluorine, chlorine, bromine, NO.sub.2, CN, OH, COOH, (C.sub.1 -C.sub.6)-alkyl, (C.sub.1 -C.sub.6)-alkoxy, C(O)--O--(C.sub.1 -C.sub.6)-alkyl, C(O)--(C.sub.1 -C.sub.6)-alkyl, O--C(O)--(C.sub.1 -C.sub.6)-alkyl, and X is a leaving group.